A number of previous studies have indicated that cardiomyocyte death characteristic of apoptosis occurs in response to ischemia/reperfusion (I/R). These have also reported the pathology of cardiopathies observed under such conditions (Bialik, S. et al., 1997; Gottlieb, R. A. et al., 1994; Maulik, N. et al., 1999; Tanaka, M. et al., 1994). Since apoptosis occurs within 24 hours after ischemia/reperfusion and is accompanied by a massive loss of cardiomyocytes, it considerably increases the risk of developing cardiac dysfunctions (Colucci, W. S., 1996). Therefore, if cardiomyocyte apoptotic death could be inhibited, ischemia/reperfusion-based cardiac symptoms and dysfunctions including myocardial damages such as myocardial infarction and angina pectoris could be reduced. Recently, the importance of apoptosis in cell death following reperfusion was demonstrated, and several methods and strategies for inhibiting apoptotic cell death have been proposed. These methods include pharmaceutical methods, growth factor-mediated methods, and genetic interference (Eefting, F. et al., 2004).
Midkine (MK) is a 13 kDa heparin-binding growth factor, which is rich in basic amino acids and cysteines (Kadomatsu, K. et al., 1988; Tomomura, M. et al., 1990). Since the amino acid sequences of MK and pleiotrophin/heparin-binding growth-associated molecule (PTN/HB-GAM) are 50% homologous, these molecules can be distinguished from molecules such as fibroblast growth factors (FGFs), and hepatocyte growth factors (HGFs) (Li, Y. S. et al., 1990; Merenmies, J. et al., 1990; Muramatsu, T., 1993). MK expression in adult tissues is strictly limited, and in mice, this proteinaceous factor is expressed only in the kidneys and the uterus at high concentrations. MK and PTN/HB-GAM both have neurotrophic activity, and may be associated with nerve growth and tumor growth. In cultured nerve cells (neurons), MK inhibits caspase-dependent apoptosis via activation of ERK, a type of mitogen-activated protein kinase (Owada, K. et al., 1999). Another effect of MK is to protect cells from damage by enhancing the expression of Bcl-2 (Qi, M. et al., 2000).
Myocardial damages such as ischemic heart disease and dilated cardiomyopathy are fatal diseases. Even if life could be sustained, heart failure is very likely to occur and the quality of life will be considerably restricted. Particularly in severe heart failure, the only effective method at present is heart surgery that has donor availability and histocompatibility issues, and there are no other effective radical methods of treatment.
Ikematsu et al. have previously proposed therapeutic agents or preventive agents for ischemic diseases, which comprise MK as an active ingredient (see Patent Document 1).
[Patent Document 1] WO99/16463 pamphlet